本文選題：銥(Ⅲ)配合物　切入點：鉑(Ⅱ)配合物　出處：《復旦大學》2013年碩士論文　論文類型：學位論文

【摘要】：癌癥是威脅人類健康的全球頭號殺手,以順鉑、卡鉑、奧沙利鉑為代表的鉑(Ⅱ)類金屬配合物抗腫瘤藥由于其抗癌譜廣、作用機制獨特、毒性譜特殊,在超過50%的臨床聯合化療方案中使用。盡管鉑(Ⅱ)配合物在惡心腫瘤的臨床治療中取得了巨大的成功,但其存在毒副作用大、易產生交叉耐藥的嚴重缺陷,進一步研發(fā)具有高效低毒、能克服順鉑類交叉耐藥的新型金屬配合物的抗癌藥的需求顯得尤為迫切。 本論文基于經典鉑(Ⅱ)類抗癌藥作用機制和構效關系的研究成果,根據非鉑類金屬配合物抗腫瘤活性研究的文獻調研結果,選擇金屬配合物抗腫瘤研究中較少涉及到的銥(Ⅲ)作為配合物的中心金屬原子,結合本課題組前期工作基礎,首次創(chuàng)新引入手性鄰二胺作為三價銥配合物的配體,重點設計合成了22個C2對稱性手性鄰二胺配體銥(Ⅲ)配合物和13個非C2對稱性手性鄰二胺配體銥(Ⅲ)合物,全部為新化合物。此外,還擴展了配合物配體類型,設計合成了13個具有含氮芳香雙齒配體溶劑單齒配體結構的銥(Ⅲ)配合物,其中7個為新化合物。所有配合物結構均經R、MS及(或)NMR確證,其中配合物trans-68d的立體結構還經X-射線單晶衍射得到確認。針對以上三類銥(Ⅲ)配合物進行了系統的抗腫瘤活性及構效關系研究,以期發(fā)現高效低毒、完全打破順鉑類結構框架的新型銥(Ⅲ)配合物抗腫瘤新藥。此外,完善了本課題組前期研究中關于抗腫瘤(R,R)-非C2對稱性鄰二胺配體鉑(Ⅱ)配合物的工作,補充合成了12個手性鄰二胺配體鉑(Ⅱ)配合物(9個為新化合物),進行了系統的構效關系研究。 選擇A549(非小細胞肺癌)、A2780(卵巢癌)、KB(口腔表皮癌)、MDA-MB-231(乳腺癌)四種人實體瘤細胞株,對所合成的銥(Ⅲ)配合物了進行體外抗腫瘤活性測試。結果顯示,三類銥(Ⅲ)配合物中,以Q對稱性手性鄰二芳胺配體系列的銥(Ⅲ)配合物的活性最好。該系列中有6個配合物對所測四種腫瘤細胞中的至少三種顯示出與陽性對照藥奧沙利鉑相近甚至較之更強的抗腫瘤活性,并且配體的手性碳構型對配合物的抗腫瘤活性有重要影響：以互為對映異構體的兩個C2對稱性鄰二芳胺為配體形成的相應銥(Ⅲ)配合物,(R,R)-構型配體的配合物抗腫瘤活性遠大于(S,S)-構型異構體。此外,還對其中活性較好的代表性化合物tran-68d進行了初步的作用機制研究及急性毒性評價,結果顯示trans-68d通過p53介導的細胞凋亡通路殺傷A2780細胞,并且經ICR小鼠腹腔注射該配合物LDso值遠高于奧沙利鉑。 最后,本文分別從三個類型的銥(Ⅲ)配合物中選取了共9個化合物,利用激光共聚焦熒光顯微鏡對其進行了KB腫瘤細胞內熒光成像研究,結果顯示其中7個配合物能發(fā)出不同強度的熒光且主要分布于細胞胞漿區(qū),為我們日后探索藥靶提供了一定基礎。 本論文的研究工作以新型手性鄰二胺配體銥(Ⅲ)配合物的抗腫瘤活性研究為重點,涵蓋了化學合成,體內外活性測試,毒性評價、作用機制研究等基礎研究。該研究內容已獲得國家自然科學基金以及上海市科委基金的資助,對開發(fā)具有我國自主知識產權的新型銥(Ⅲ)配合物抗腫瘤藥物有非常積極的意義。本論文相關內容已發(fā)表SCI學術論文一篇,申請專利一項。
[Abstract]:Cancer is a threat to human health in the world's biggest killer, cisplatin, carboplatin, oxaliplatin as the representative of the platinum (II) metal complexes antitumor drugs because of its wide anticancer spectrum, unique mechanism, toxicity profile special use in clinical chemotherapy of more than 50%. As Guan Bo (II) with clinical treatment. The nausea of tumor was a huge success, but it has side effects, serious defects of cross resistance, further research and development of high efficiency and low toxicity of anticancer drugs, the new metal platinum can overcome the cross resistance with the demand is particularly urgent.
This paper is based on the classic platinum (II) type of anticancer drug mechanism and structure-activity relationship research results, according to the literature research results on antitumor activity of non platinum metal complexes, metal complexes are less involved in the anti-tumor research of iridium (III) complexes with metal atoms in the heart as the our previous work, the first innovation introduced two amine as chiral vicinal trivalent iridium complexes with ligands, 22 C2 symmetric chiral vicinal two amine ligand synthesized iridium (III) complexes with the focus on the design of C2 and 13 non symmetry of two adjacent chiral amine ligand iridium (III) complexes, all of them are new compounds. In addition, also extends the ligand type with 13 aromatic nitrogen bidentate ligand solvent monodentate ligand structure of the synthesized iridium (III) complexes, including 7 new compounds. All complexes were confirmed by R, MS and (or) NMR spectra, complexes trans The three-dimensional structure of -68d was confirmed by X- ray diffraction. For the above three types of iridium (III) complexes were the antitumor activity and structure-activity relationship research, in order to find the high efficiency and low toxicity, completely breaking the framework of platinum iridium (III) complexes with antitumor drugs. In addition, perfect a tumor in the previous study (R, R) - C2 non symmetry of two adjacent amine ligands of platinum (II) complexes, 12 chiral vicinal amine ligands were synthesized on two platinum (II) complexes (9 compounds), studied the structure-activity relationship of system.
閫夋嫨A549(闈炲皬緇嗚優(yōu)鑲虹檶),A2780(鍗靛發(fā)鐧，

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